1. Field of the Invention
The present invention relates generally to mass spectrometry, and in particular, to a method, apparatus, and article of manufacture for integrating a differential mobility analyzer with a mass spectrometer.
2. Description of the Related Art
(Note: This application references a number of different publications as indicated throughout the specification by reference numbers enclosed in brackets, e.g., [x]. A list of these different publications ordered according to these reference numbers can be found below in the section entitled “References.” Each of these publications is incorporated by reference herein.)
Two dimensional separation in mass spectrometry (MS) is an area under constant development. The analysis of mixtures often demands separation of the mixture before final analysis owing to the complexity of the mixture. Many techniques in mass spectrometry already exist and are well suited to mixture analysis. Liquid chromatography-mass spectrometry (LC-MS) is a widely used technique that has the greatest utility in pre-separating protein digests prior to mass spectrometry analysis. Ion mobility spectrometry mass spectrometry (IMS-MS) is an example of a two dimensional separation where the first dimension is the mobility of the ion and the second dimension is the mass of that ion.
The aforementioned preseparations operate in the time domain wherein a sample that is introduced at the entrance of the preseparation device are separated into fractions that arrive at the mass spectrometer entrance at times that vary according to specific physico-chemical properties of the analyte. A fast mass spectrometric analytical method such as time-of-flight mass spectrometry may be able to analyze the entire range of possible mass-to-charge-ratios on a time that is short compared to the time resolution of the preseparation method, but slower mass spectrometric methods may only be able to resolve a limited range of mass to charge ratios. If, however, the preseparation is capable of continuously transmitting a selected fraction of the sample, slower mass spectrometric methods may be able to resolve all of the components of the fraction. One example of such a continuous preseparation is field assymetric waveform ion mobility spectrometry (FAIMS™) which transmits molecules with mobilities within a narrow range of values to the mass spectrometer for sufficient time to resolve the analytes of interest within selected ion mobility fractions of the original sample.
While research implementations of mobility-MS experiments have been in existence for some time, commercial instrumentation for achieving mass-mobility measurements is nonetheless part of the state of the art in mass spectrometry instrumentation. Instrument companies have invested considerable dollars in the development of the latest class of instruments with mobility front ends. Advances in electronics and fabrication methods have finally enabled the mass production of such instruments on a scale commensurate with implementation in commercial laboratories. Examples of such instruments include Waters™ SYNAPT™ instruments and Thermo Scientific™ instruments using a field asymmetric waveform ion mobility spectrometry (FAIMS™) interface, as well as a number of instruments from smaller manufacturers. The fact that such research and development funding has been committed to the development of mobility-mass measurement is indicative that such instruments are desired and must continually be developed.
Accordingly, what is needed is a hybrid mass mobility instrument with a front-end mobility separation device. To better understand the problems of the prior art, a description of prior art mass spectrometry techniques is useful.
Mass spectrometry is an analytical technique used to identify unknown compounds, the isotopic composition of elements in a molecule and to determine the structure of a compound. Such identification is performed by measuring the mass-to-charge ratio of charged particles which can be used to determine the particle's mass, the composition of a sample, and/or the chemical structure of the sample/molecule.
In an MS process, a sample is loaded onto an instrument where it is vaporized (i.e., transitioned into a gas from a solid or liquid). The result is then ionized by a variety of methods to form charged particles (ions). The ions are separated by their mass-to-charge ratio in an analyzer, detected, and the ion signal is processed into mass spectra.
An MS instrument used to perform the above process may include an ion source, a mass analyzer, and a detector. The ion source is used to perform the vaporization and the ionization of the material under analysis (the analyte). Electrospray ionization (EI), where liquid containing the analyte is dispersed by electrospray into a fine aerosol, may be used during the ionization process. The ions are transported to the mass analyzer that sorts the ions by their masses (e.g., by applying electromagnetic fields). The detector measures the quantity of ions.
As described above, chromatographic techniques may be combined with MS to separate different compounds before analysis by the MS. LC-MS separates a liquid analyte (e.g., in combination with ES) before introducing the compound to the ion source and MS. IMS-MS first separates ions by drift time through a neutral gas under an applied electrical potential gradient before being introduced into an MS.
Embodiments of the present invention provide the ability to perform mobility separation before mass analysis by an MS. As set forth in the detailed description below, various different types of differential mobility analyzers (DMAs) may be used. For example, radial DMAs (RDMAs) may be used in one or more embodiments of the invention. Previously, a nano-RDMA device was presented and mobility values for various tetraalkylammonium ions were reported [1][7][8]. The previous experiment used an electrometer detection scheme where all ion current exiting the device was measured. However, prior art systems fail to integrate nano-RDMAs with an MS in an effective manner. Further, the prior art fails to integrate MS with DMAs that operate with flow rates that are compatible with general analytical laboratory operations.